Hugo R. Arias, HR, Ruo-Xu Gu, R, Feuerbach, Dominik and Dong-Qing Wei, W (2010) Different Interaction between the Agonist JN403 and the Competitive Antagonist Methyllycaconitine with the Human α7 Nicotinic Acetylcholine Receptor. Biochemistry.

Abstract

The interaction of the agonist JN403 with the human (h) α7 nicotinic acetylcholine receptor (AChR) was compared to that for several ligands including the antagonist methyllycaconitine (MLA). The results established that both JN430 and MLA have a cationic center and a hydrophobic group as pharmacophores, which interact with the aromatic cage and the hydrophobic cavity, respectively, found in both hα7 and hα3β4 AChRs. The importance of the cationic center for the formation of cation-π interactions was apparent when gx-50, gx-52, and open3d-51265, which do not have this cation center, failed to induce Ca2+ influx in GH3-hα7 cells, and to inhibit [3H]MLA and [3H]epibatidine binding to the hα7 and hα3β4 AChRs, respectively. Moreover, JN403 binds to hα7 AChRs with ~90-fold higher specificity compared to that for hα3β4 AChRs, due to more hydrogen bonds between the acidamide group (another pharmacophore) of JN403 and the hα7 sites and to the electrostatic repulsion between the positively charged residues around the hα3β4 sites and the cationic center of JN403. MLA pre-incubation inhibits JN403-induced Ca2+ influx in GH3-hα7 cells with 160-fold higher potency compared to that when MLA is co-injected with JN403, probably because MLA (more specifically the 3-methyl-2,5-dioxopyrrole ring and the B, C, D rings) stabilizes the resting conformational state.

Item Type:	Article
Date Deposited:	26 Apr 2016 23:46
Last Modified:	26 Apr 2016 23:46
URI:	https://oak.novartis.com/id/eprint/2104